Efficacy and Safety Trial of Verubecestat (MK-8931) in Participants With Prodromal Alzheimer's Disease (MK-8931-019)

Phase 3TerminatedNCT01953601

Merck Sharp & Dohme LLC1,454 enrolled

Overview

This study consists of two parts, Part 1 and Part 2. Part 1 assesses the efficacy and safety of verubecestat (MK-8931) compared with placebo administered for 104 weeks in the treatment of amnestic mild cognitive impairment (aMCI) due to Alzheimer's Disease (AD), also known as prodromal AD. Participants are randomized to receive placebo, or 12 mg or 40 mg verubecestat, once daily. The primary study hypothesis for Part 1 is that ≥1 verubecestat dose is superior to placebo with respect to the change from baseline in the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB) score at 104 weeks. Participants completing Part 1 may choose to participate in Part 2, which is a long term double-blind extension to assess efficacy and safety of verubecestat administered for up to an additional 260 weeks. In Part 2, all participants receive either 12 mg or 40 mg verubecestat, once daily.

As a result of protocol amendment, Study Part 2 will contain a Positron Emission Tomography (PET) imaging substudy to assess regional neurofibrillary tangle (NFT) expression.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

1,454

Conditions

Amnestic Mild Cognitive Impairment Alzheimer's Disease

Eligibility

Sex: ALLMin age: 50 YearsMax age: 85 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Diagnosis of prodromal AD, including the following: 1. History of subjective memory decline with gradual onset and slow progression for at least one year corroborated by an informant, 2. Objective impairment in episodic memory by memory test performed at Screening, 3. Does not meet criteria for dementia, AND 4. Positive Screening amyloid imaging PET scan using \[18F\]flutametamol tracer or positive Screening CSF tau:amyloid-β42 (Aβ42) ratio (Participants with a prior positive amyloid imaging PET scan or a Screening PET scan with florbetaben or florbetapir may be enrolled without a Screening flutemetamol scan with Sponsor approval) 2. Able to read at a 6th grade level or equivalent 3. If participant is receiving an acetylcholinesterase inhibitor or memantine, the dose must have been stable for at least three months before Screening 4. Must have a reliable and competent trial partner/informant who has a close relationship with the participant and is willing to accompany the participant to all required trial visits, and to monitor compliance of the administration of the trial medication Inclusion Criteria for Extension Period (Part 2): 1. Tolerated study drug and completed the initial 104-week period of the trial (Part 1) 2. Participant must have a reliable and competent trial partner who must have a close relationship with the subject Exclusion Criteria: 1. History of stroke 2. Evidence of a clinically relevant neurological disorder other than the disease being studied (i.e., prodromal AD) 3. History of seizures or epilepsy within the last 5 years 4. Evidence of a clinically relevant or unstable psychiatric disorder, excluding major depression in remission 5. Participant is at imminent risk of self-harm or of harm to others 6. History of alcoholism or drug dependency/abuse within the last 5 years before Screening 7. Participant does not have a magnetic resonance imaging (MRI) scan obtained within 12 months of Screening and is unwilling or not eligible to undergo an MRI scan at the Screening Visit. With Sponsor approval, a head computed tomography (CT) scan may be substituted for MRI scan to evaluate eligibility 8. History of hepatitis or liver disease that has been active within the 6 months prior to Screening 9. Recent or ongoing, uncontrolled, clinically significant medical condition within 3 months of Screening 10. History of malignancy occurring within the 5 years before Screening, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or localized prostate carcinoma 11. Clinically significant vitamin B12 or folate deficiency in the 6 months before Screening 12. Use of any investigational drugs or participation in clinical trials within the 30 days before Screening 13. History of a hypersensitivity reaction to more than three drugs 14. Has human immunodeficiency virus (HIV) by medical history 15. Participant is unwilling or has a contraindication to undergo PET scanning including but not limited to claustrophobia, excessive weight or girth 16. History or current evidence of long QT syndrome, corrected QT (QTc) interval ≥470 milliseconds (for male participants) or ≥480 milliseconds (for female participants), or torsades de pointes 17. Close family member (including the trial partner, spouse or children) who is among the personnel of the investigational or sponsor staff directly involved with this trial Exclusion Criteria for Extension Period (Part 2): 1. Participant is at imminent risk of self-harm or of harm to others 2. Has developed a recent or ongoing, uncontrolled, clinically significant medical or psychiatric condition 3. Results of safety assessments (e.g., laboratory tests) performed in participant at end of Part 1 that are clinically unacceptable to the Investigator 4. Has developed a form of dementia that is not AD 5. Has progressed to dementia due to AD per investigator diagnosis in the initial 104-week study (Part 1). Exclusion Criteria for NFT PET Substudy (Part 2): 1\. Had one or two PET scans with MK-6240 in the initial 104-week study.

Outcomes

Primary Outcomes

Part 1 (Base Study). Least Squares Mean (LSM) Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score at Week 104

LSM change from baseline at week 104 was assessed for CDR-SB score, a clinical rating of global cognitive function, comprised of 6 domains: memory; orientation; judgment and problem solving; community affairs; home and hobbies; and personal care. For each domain, the degree of impairment is assessed by a semi-structured interview of the participant as well as the participant's caregiver. For each domain, potential scores range from 0 (no impairment) to 3 (severe impairment). Individual domain scores are summed to a total CDR-SB score (range: 0-18). Higher scores indicate more severe cognitive impairment. Further, increases in cognitive impairment would be reflected by increases in CDR-SB score.

Time frame: Baseline and Week 104 in Part 1

Part 2 (Extension Study). Mean Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score at Week 130

Mean change from baseline at week 130 was assessed for CDR-SB score, a clinical rating of global cognitive function, comprised of 6 domains: memory; orientation; judgment and problem solving; community affairs; home and hobbies; and personal care. For each domain, the degree of impairment is assessed by a semi-structured interview of the participant as well as the participant's caregiver. For each domain, potential scores range from 0 (no impairment) to 3 (severe impairment). Individual domain scores are summed to a total CDR-SB score (range: 0-18). Higher scores indicate more severe cognitive impairment. Further, increases in cognitive impairment would be reflected by increases in CDR-SB score. Per protocol, baseline refers to the baseline measurement obtained in Part 1.

Time frame: Baseline and Week 130 (i.e., Week 26 of Part 2)

Part 1 (Base Study). Percentage of Participants Who Experienced ≥1 Adverse Event (AE)

The percentage of participants experiencing an AE in Part 1 was assessed. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product is also an AE.

Time frame: Up to Week 106 (up to 2 weeks following cessation of study treatment in Part 1)

Part 1 (Base Study). Percentage of Participants Who Discontinued From Study Drug Due to an Adverse Event (AE)

The percentage of participants who discontinued from study drug due to an AE in Part 1 was assessed. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product is also an AE.

Time frame: Up to Week 104 in Part 1

Part 2 (Extension Study). Percentage of Participants Who Experienced ≥1 Adverse Event (AE)

The percentage of participants experiencing an AE in Part 2 was assessed. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product is also an AE.

Time frame: From Week 104 (start of treatment in Part 2) up to Week 210 (up to 2 weeks following cessation of study treatment in Part 2)

Part 2 (Extension Study). Percentage of Participants Who Discontinued From Study Drug Due to an Adverse Event (AE)

The percentage of participants who discontinued from study drug due to an AE in Part 2 was assessed. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product is also an AE.

Time frame: From Week 104 (start of treatment in Part 2) up to Week 208 (i.e., up to Week 104 in Part 2)

Secondary Outcomes

Part 1 (Base Study). Event-Rate Per 100 Participant Years for Progression to a Clinical Diagnosis of Probable AD Dementia

The event-rate per 100 participant-years for progression to a clinical diagnosis of probable AD dementia was calculated. Adjudication of a potential case was triggered if either: 1) in the investigator's own expert judgment, they think the participant may have progressed to dementia and/or 2) the participant's CDR-SB score is ≥2 points higher compared to baseline. Cases of progression to probable AD dementia confirmed by an external adjudication committee were counted as events in the analysis. The event-rate was calculated as the number of events divided by total follow-up time (participant-years) x 100; unit of measure is event-rate / 100 participant-years.

Time frame: Up to Week 104 in Part 1

Part 1 (Base Study). Estimated Least Squares Mean Difference Between the Last (Week 104) and First (Week 13) Post-dose CDR-SB Assessment

LSM difference between weeks 104 and 13 was estimated for CDR-SB score, a clinical rating of global cognitive function, comprised of 6 domains: memory; orientation; judgment / problem solving; community affairs; home / hobbies; and personal care. For each domain, degree of impairment is scored by a semi-structured interview of the participant and the participant's caregiver (domain score range: 0 \[no impairment\] to 3 \[severe impairment\]). Domain scores sum to a total CDR-SB score (range: 0-18); higher scores indicate more severe cognitive impairment. Further, increased cognitive impairment is reflected by higher CDR-SB scores; larger differences between week 104 and week 13 scores indicates accelerated AD progression.

Time frame: Week 13 and Week 104 in Part 1

Part 1 (Base Study). Least Squares Mean Change From Baseline in the 3-Domain Composite Cognition Score (CCS-3D) at Week 104

CCS-3D is composed of individual cognitive tests, grouped into 3 domains: 1) episodic memory; 2) executive function; and 3) attention/processing speed. For each cognitive test, a z-score (Z) is calculated at each time point \[Z = (observed value - study population mean at baseline) / study population standard deviation at baseline\]. These individual Zs are first combined into domain-specific Zs, and then into a composite Z, (i.e. CCS-3D). Theoretically, 99.9% of CCS-3D will be ± 3; more positive CCS-3D indicate greater cognitive impairment relative to the total study population at baseline. Further, negative changes in CCS-3D over time indicate improved cognition relative to the total study population at baseline.